1. Field of the Invention
The present invention relates generally to medical devices and methods. More particularly, the present invention provides luminal prostheses, such as vascular stents and grafts, which allow for controlled substance delivery for inhibiting restenosis in a blood vessel following balloon angioplasty or other interventional treatments.
A number of percutaneous intravascular procedures have been developed for treating stenotic atherosclerotic regions of a patient""s vasculature to restore adequate blood flow. The most successful of these treatments is percutaneous transluminal angioplasty (PTA). In PTA, a catheter, having an expansible distal end usually in the form of an inflatable balloon, is positioned in the blood vessel at the stenotic site. The expansible end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region. Other procedures for opening stenotic regions include directional arthrectomy, rotational arthrectomy, laser angioplasty, stenting, and the like. While these procedures have gained wide acceptance (either alone or in combination, particularly PTA in combination with stenting), they continue to suffer from significant disadvantages. A particularly common disadvantage with PTA and other known procedures for opening stenotic regions is the frequent occurrence of restenosis.
Restenosis refers to the re-narrowing of an artery after an initially successful angioplasty. Restenosis afflicts approximately up to 50% of all angioplasty patients and is the result of injury to the blood vessel wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by smooth muscle cell proliferation referred to as xe2x80x9chyperplasiaxe2x80x9d in the region traumatized by the angioplasty. This proliferation of smooth muscle cells re-narrows the lumen that was opened by the angioplasty within a few weeks to a few months, thereby necessitating a repeat PTA or other procedure to alleviate the restenosis.
A number of strategies have been proposed to treat hyperplasia and reduce restenosis. Previously proposed strategies include prolonged balloon inflation during angioplasty, treatment of the blood vessel with a heated balloon, treatment of the blood vessel with radiation following angioplasty, stenting of the region, and other procedures. While these proposals have enjoyed varying levels of success, no one of these procedures is proven to be entirely successful in completely avoiding all occurrences of restenosis and hyperplasia.
As an alternative or adjunctive to the above mentioned therapies, the administration of therapeutic agents following PTA for the inhibition of restenosis has also been proposed. Therapeutic treatments usually entail pushing or releasing a drug through a catheter or from a stent. Of particular interest herein, stents may incorporate a biodegradable or nondegradable matrix to provide programmed or controlled release of therapeutic agents within a blood vessel. Biodegradable or bioerodible matrix materials employed for controlled release of drugs may include poly-1-lactic acid/poly-e-caprolactone copolymer, polyanhydrides, polyorthoesters, polycaprolactone, poly vinly acetate, polyhydroxybutyrate/polyhyroxyvalerate copolymer, polyglycolic acid, polyactic/polyglycolic acid copolymers and other aliphatic polyesters, among a wide variety of polymeric substrates employed for this purpose.
While holding great promise, the delivery of therapeutic agents for the inhibition of restenosis has not been entirely successful. In particular, the release of drugs from stents has often been characterized by inconsistent and/or ineffective results because therapeutic agents are often released before they are needed, i.e., before hyperplasia and endothelialization begin. Drug delivery before any cellular or endothelial formation may also pose serious dangers, especially when dealing with the delivery of certain toxic agents. Furthermore, a rapid initial release of drugs causes delayed endothelialization and/or enlargement of the vessel wall, as a substantial number of cells are killed with increased drug loading. The use of drug release matrices can ameliorate the rapid release problems but do not provide programmed time-delay to impact restenosis at the onset of hyperplasia.
For these reasons, it would be desirable to provide improved devices and methods for reducing and/or inhibiting restenosis and hyperplasia following angioplasty and other interventional treatments. In particular, it would be desirable to provide improved devices and methods, utilizing luminal prostheses, such as vascular stents and grafts, which provide programmed and controlled substance delivery with increased efficacy to inhibit restenosis. It would further be desirable to provide such devices and methods which would reduce and/or further eliminate drug washout and potentially provide minimal to no hindrance to endothelialization of the vessel wall. At least some of these objectives will be met by the devices and methods of the present invention described hereinafter.
2. Description of the Background Art
U.S. Pat. No. 5,283,257, suggests that a stent could be used to deliver mycophenolic acid to a blood vessel. Mycophenolic acid methods of production and uses, some of which are intravascular, are described in U.S. Pat. Nos. 6,107,052; 5,916,585; 5,807,876; 5,646,160; 5,563,146; 5,516,781; 4,786,637; 4,753,935; 4,727,069; 4,686,234; 4,234,684; 4,115,197; 3,903,071; 3,880,995; 3,868,454; 3,777,020; 3,705,946; and 3,705,894. Inhibitory effects of mycophenolic acid on human and rat aortic smooth muscle and endothelial cell proliferation is described in Mohacsi et al., J Heart and Lung Trasplant, 16, pp. 484-491 (1997). Animal models of accelerated arteriosclerosis have demonstrated that MPA could decrease the extent of smooth muscle cell proliferation in Gregory et al., Transplant Proc., 25, pp. 770 (1993). A European clinical study reported reduced incidence of acute rejection of patients undergoing kidney transplantation in the first six months after being treated with mycophenolic mofetil in Lancet, pp. 345, 1321 (1995).
Method and apparatus for releasing active substances from implantable and other devices are described in U.S. Pat. Nos. 6,096,070; 5,824,049; 5,624,411; 5,609,629; 5,569,463; 5,447,724; and 5,464,650. The use of stents for drug delivery within the vasculature are described in PCT Publication No. WO 01/01957 and U.S. Pat. Nos. 6,099,561; 6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027; 5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172; 5,837,008; 5,769,883; 5,735,811; 5,700,286; 5,679,400; 5,649,977; 5,637,113; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450; 5,419,760; 5,411,550; 5,342,348; 5,286,254; and 5,163,952. Biodegradable materials are described in U.S. Pat. Nos. 6,051,276; 5,879,808; 5,876,452; 5,656,297; 5,543,158; 5,484,584; 5,176,907; 4,894,231; 4,897,268; 4,883,666; 4,832,686; and 3,976,071. The use of hydrocylosiloxane as a rate limiting barrier is described in U.S. Pat. No. 5,463,010. Methods for coating of stents is described in U.S. Pat. No. 5,356,433. Coatings to enhance biocompatibility of implantable devices are described in U.S. Pat. Nos. 5,463,010; 5,112,457; and 5,067,491.
The disclosure of this application is related to the disclosures of the following copending applications being filed on the same day: U.S. patent application Ser. Nos. 09/783,253; 09/783,254; and 09/782,804.
The full disclosures of each of the above references are incorporated herein by reference.
The present invention provides improved devices and methods for inhibiting restenosis and hyperplasia after intravascular intervention. In particular, the present invention provides luminal prostheses which allow for programmed and controlled mycophenolic acid delivery with increased efficiency and/or efficacy to selected locations within a patient""s vasculature to inhibit restenosis. Moreover, the present invention provides minimal to no hindrance to endothelialization of the vessel wall.
The term xe2x80x9cintravascular interventionxe2x80x9d includes a variety of corrective procedures that may be performed to at least partially resolve a stenotic, restenotic, or thrombotic condition in a blood vessel, usually an artery, such as a coronary artery. Usually, the corrective procedure will comprise balloon angioplasty. The corrective procedure could also comprise directional atherectomy, rotational atherectomy, laser angioplasty, stenting, or the like, where the lumen of the treated blood vessel is enlarged to at least partially alleviate a stenotic condition which existed prior to the treatment.
Mycophenolic acid is an immunosuppressive drug produced by the fermentation of several penicillium brevi-compactum and related species (The Merk Index, Tenth Edition, 1983). It has a broad spectrum of activities, specific mode of action, and is tolerable in large does with minimal side effects, Epinette et al., Journal of the American Academy of Dermatology, 17, pp. 962-971 (1987). Mycophenolic acid has been shown to have anti-tumor, anti-viral, anti-psoriatric, immunosuppressive, and anti-inflammatory activities, Lee et al., Pharmaceutical Research, 2, pp. 161-166 (1990), along with antibacterial and antifungal activities, Nelson et al., Journal of Medicinal Chemistry, 33, pp. 833-838 (1990). Of particular interest to the present invention, animal studies of accelerated arteriosclerosis have demonstrated that mycophenolic acid could also decrease the extent of smooth muscle cell proliferation, Gregory et al., Transplant Proc., 25, pp. 770 (1993).
Mycophenolic acid acts by inhibiting inosine monophosphate dehydrogenase and guanosine monophosphate synthetase enzymes in the de novo purine biosynthesis pathway. This may cause the cells to accumulate in the G1-S phase of the cell cycle and thus result in inhibition of DNA synthesis and cell proliferation (hyperplasia). In the present application, the term xe2x80x9cmycophenolic acidxe2x80x9d is used to refer to mycophenolic acid itself and to pro-drugs and/or pharmaceutically derivatives thereof (precursor substances that are converted into an active form of mycophenolic acid in the body). For example, a pro-drug such as mycophenolate mofetil may be biotransformed or metabolically converted to a biologically active form of mycophenolic acid when administered in the body. A number of derivatives of mycophenolic acid are taught in U.S. Pat. Nos. 4,786,637, 4,753,935, 4,727,069, 4,686,234, 3,903,071, and 3,705,894, all incorporated herein by reference, as well as pharmaceutically acceptable salts thereof.
In a first aspect of the present invention, a vascular prosthesis comprises an expansible structure which is implantable within a body lumen and means on or within the structure for releasing mycophenolic acid at a rate selected to minimize and/or inhibit smooth muscle cell proliferation. Mycophenolic acid release will typically be at rates in a range from 5 xcexcg/day to 200 xcexcg/day, preferably in a range from 10 xcexcg/day to 60 xcexcg/day. The total amount of mycophenolic acid released will typically be in a range from 100 xcexcg to 10 mg, preferably in a range from 300 xcexcg to 2 mg, more preferably in a range from 500 xcexcg to 1.5 mg. Thus, the present invention improves the efficiency and efficacy of mycophenolic acid delivery by releasing mycophenolic acid at a rate and/or time which inhibits smooth muscle cell proliferation.
The expansible structure may be in the form of a stent, which additionally maintains luminal patency, or may be in the form of a graft, which additionally protects or enhances the strength of a luminal wall. The expansible structure may be radially expansible and/or self-expanding and is preferably suitable for luminal placement in a body lumen. The body lumen may be any blood vessel in the patient""s vasculature, including veins, arteries, aorta, and particularly including coronary and peripheral arteries, as well as previously implanted grafts, shunts, fistulas, and the like. It will be appreciated that the present invention may also be applied to other body lumens, such as the biliary duct, which are subject to excessive neoplastic cell growth, as well as to many internal corporeal tissue organs, such as organs, nerves, glands, ducts, and the like. An exemplary stent for use in the present invention is described in co-pending application No. 09/565,560, the full disclosure of which is incorporated herein by reference.
In a first embodiment, the means for releasing mycophenolic acid comprises a matrix formed over at least a portion of the structure. The matrix may be composed of a material which is degradable, partially degradable, nondegradable polymer, synthetic, or natural material. Mycophenolic acid may be disposed within the matrix or adjacent to the matrix in a pattern that provides the desired release rate. Alternatively, mycophenolic acid may be disposed on or within the expansible structure adjacent to the matrix to provide the desired release rate. Suitable biodegradable or bioerodible matrix materials include polyanhydrides, polyorthoesters, polycaprolactone, poly vinly acetate, polyhydroxybutyrate-polyhyroxyvalerate, polyglycolic acid, polyactic/polyglycolic acid copolymers and other aliphatic polyesters, among a wide variety of polymeric substrates employed for this purpose. A preferred biodegradable matrix material of the present invention is a copolymer of poly-1-lactic acid and poly-e-caprolactone. Suitable nondegradable matrix materials include polyurethane, polyethylene imine, cellulose acetate butyrate, ethylene vinyl alcohol copolymer, or the like.
The polymer matrix may degrade by bulk degradation, in which the matrix degrades throughout, or preferably by surface degradation, in which a surface of the matrix degrades over time while maintaining bulk integrity. Hydrophobic matrices are preferred as they tend to release mycophenolic acid at the desired release rate. Alternatively, a nondegradable matrix may release the substance by diffusion.
In some instances, the matrix may comprise multiple adjacent layers of same or different matrix material, wherein at least one layer contains mycophenolic acid and another layer contains mycophenolic acid, at least one substance other than mycophenolic acid, or no substance. For example, mycophenolic acid disposed within a top degradable layer of the matrix is released as the top matrix layer degrades and a second substance disposed within an adjacent nondegradable matrix layer is released primarily by diffusion. In some instances, multiple substances may be disposed within a single matrix layer.
The at least one substance other than mycophenolic acid may comprise an immunosuppressive agent selected from the group consisting of rapamycin, mizoribine, riboflavin, tiazofurin, methylprednisolone, FK 506, zafurin, and methotrexate. Such immunosuppressive substances, like mycophenolic acid, may be useful in the present invention to inhibit smooth muscle cell proliferation. Alternatively, the at least one substance other than mycophenolic acid may comprise at least one agent selected from the group consisting of anti-platelet agent (e.g., plavax, ticlid), anti-thrombotic agent (e.g., heparin, heparin derivatives), and IIb/IIIa agent (e.g., integrilin, reopro). The agent may also be a pro-drug of any of the above listed agents.
Additionally, a rate limiting barrier may be formed adjacent to the structure and/or the matrix. Such rate limiting barriers may be nonerodible or nondegradable, such as silicone, polytetrafluorethylene (PTFE), parylene, and PARYLAST(trademark), and control the flow rate of release passing through the rate limiting barrier. In such a case, mycophenolic acid may be released by diffusion through the rate limiting barrier. Furthermore, a biocompatible or blood compatible layer, such as polyethylene glycol (PEG), may be formed over the matrix or rate limiting barrier to make the delivery prosthesis more biocompatible.
In another embodiment, the means for releasing the substance may comprise a rate limiting barrier formed over at least a portion of the structure. Mycophenolic acid may be disposed within the barrier or adjacent to the barrier. The rate limiting barrier may have a sufficient thickness so as to provide the desired release rate of mycophenolic acid. Rate limiting barriers will typically have a total thickness in a range from 0.01 micron to 100 microns, preferably in a range from 0.1 micron to 10 microns, to provide mycophenolic acid release at the desired release rate. The rate limiting barrier is typically nonerodible such as silicone, PTFE, PARYLAST(trademark), polyurethane, parylene, or a combination thereof and mycophenolic acid release through such rate limiting barriers is usually accomplished by diffusion. In some instances, the rate limiting barrier may comprise multiple adjacent layers of same or different barrier material, wherein at least one layer contains mycophenolic acid and another layer contains mycophenolic acid, at least one substance other than mycophenolic acid, or no substance. Multiple substances may also be contained within a single barrier layer.
In yet another embodimnet, the means for releasing the substance comprises a reservoir on or within the structure containing mycophenolic acid and a cover over the reservoir. The cover may be degradable or partially degradable over a preselected time period so as to provide the desired mycophenolic acid release rate. The cover may comprise a polymer matrix, as described above, which contains mycophenolic acid within the reservoir. A rate limiting barrier, such as silicone, may additionally be formed adjacent to the reservoir and/or the cover, thus allowingmycophenolic acid to be released by diffusion through the rate limiting barrier. Alternatively, the cover may be a nondegradable matrix or a rate limiting barrier.
Another vascular prosthesis comprises an expansible structure which is implantable within a body lumen and a rate limiting barrier on the structure for releasing mycophenolic acid at a rate selected to inhibit smooth muscle cell proliferation. The barrier comprises multiple layers, wherein each layer comprises PARYLAST(trademark) or parylene and has a thickness in a range from 50 nm to 10 microns. At least one layer contains mycophenolic acid and another layer contains mycophenolic acid, at least one substance other than mycophenolic acid, or no substance.
Yet another vascular prosthesis comprises an expansible structure, a source of mycophenolic acid on or within the structure, and a source of at least one other substance in addition to mycophenolic acid on or within the structure. The mycophenolic acid is released from the source when the expansible structure is implanted in a blood vessel. The at least one additional substance is released from the source when the expansible structure is implanted in a blood vessel. Each source may comprise a matrix, rate limiting membrane, reservoir, or other rate controlling means as described herein. The at least one additional substance may be an immunosuppressive substance selected from the group consisting of rapamycin, mizoribine, riboflavin, tiazofurin, methylprednisolone, FK 506, zafurin, and methotrexate. Optionally, the at least one additional substance may comprise at least one agent selected from the group consisting of anti-platelet agent, anti-thrombotic agent, and IIb/IIIa agent.
In another aspect of the present invention, methods for inhibiting restenosis in a blood vessel following recanalization of the blood vessel are provided. For example, one method may include implanting a vascular prosthesis in the body lumen to prevent reclosure of the blood vessel. Mycophenolic acid is then released at a rate selected to inhibit smooth muscle cell proliferation. The releasing comprises delaying substantial release of mycophenolic acid for at least one hour following implantation of the prosthesis. The inhibiting release may comprise slowing release from a reservoir with a material that at least partially degrades in a vascular environment over said one hour. In some instances, release may be slowed with a matrix that at least partially degrades in a vascular environment over said one hour. In other instances, release may be slowed with a nondegradable matrix or rate limiting barrier that allows diffusion of mycophenolic acid through said nondegradable matrix or barrier after said one hour. Mycophenolic acid release will typically be at rates in a range from 5 xcexcg/day to 200 xcexcg/day, preferably in a range from 10 xcexcg/day to 60 xcexcg/day. Typically, mycophenolic acid is released within a time period of 1 day to 45 days in a vascular environment, preferably in a time period of 7 day to 21 days in a vascular environment.
The prosthesis may be coated with a matrix or barrier by spraying, dipping, deposition, or painting. Such coatings may be non-uniform. For example, the coating may be applied to only one side of the prosthesis or the coating may be thicker on one side. Likewise, the prosthesis may also incorporate mycophenolic acid by coating, spraying, dipping, deposition, chemical bonding, or painting mycophenolic acid on all or partial surfaces of the prosthesis.
Another method for inhibiting restenosis in a blood vessel following recanalization of the blood vessel comprises implanting a vascular prosthesis in the blood vessel to prevent reclosure. Mycophenolic acid and at least one other substance in addition to mycophenolic acid are released when the prosthesis is implanted in the blood vessel. The at least one additional substance may be an immunosuppressive substance selected from the group consisting of rapamycin, mizoribine, riboflavin, tiazofurin, methylprednisolone, FK 506, zafurin, and methotrexate. Preferably, the immunosuppressive substance is mizoribine or methylprednisolone. For example, mycophenolic acid may be released within a time period of 1 day to 45 days and methylprednisolone may be released within a time period of 2 days to 3 months. Optionally, the at least one additional substance may comprise at least one agent selected from the group consisting of anti-platelet agent, anti-thrombotic agent, and IIb/IIIa agent. Release of mycophenolic acid and the at least additional substance may be simultaneous or sequential.